The identity and function of regulated blood-brain barrier transporters for essential nutrients and drugs were examined in relation to aging and Alzheimer's disease. The basic amino acid transporter of the blood-brain barrier was cloned and brain choline transport was shown to be maintained with age. The substrate selectivity of the choline and neutral amino acid transporters were examined and high affinity ligands for each transporter were identified. On the basis of structure/activity studies, new drugs were developed that showed enhanced uptake into brain via carrier-mediated transport. One such compound, D,L-NAM, exhibited 20-40 fold greater brain uptake than its clinical analog, L-melphalan, and was further developed for brain antitumor testing. A similar compound, 4-chloro-kynurenine, was tested as a neuroprotective agent against excitotoxic brain damage. A sensitive secondary ion mass spectrometry method was developed to image metal distributions in human brain. Studies demonstrated no evidence for selective accumulation of aluminum in neurofibrillary tangle-bearing neurons in Alzheimer's disease.